Due to the complexity of type 1 diabetes mellitus (T1D), successful treatment will require a paradigm shifting multidisciplinary approach. The discovery of novel targets, the development of efficient drug delivery systems and the integration of state-of-the-art imaging techniques will provide real-time monitoring of both drug delivery and therapeutic outcome. Conventional therapeutics are ineffective due, in part, to the lack of directed targeting to the islets, resulting in low bioavailability. This inefficient delivey necessitates systemic administration of high doses of therapy and consequently untoward off-target effects and toxicity. To overcome these severe limitations, we propose to develop efficient delivery systems with imaging capabilities that specifically direct siRNA-based therapies to insulin-producing beta-cells. Our strategy for directed therapy is based on the exquisite specificity of RNAi for silencing harmful disease-promoting genes and our extensive experience in developing image-guided systems for siRNA delivery in various settings. Here we propose to develop an image-assisted approach for delivering siRNA therapy to endogenous beta- cells using a targeted magnetic nanoparticle platform (Nanodrug, ND) based on dextran coated iron oxide nanoparticles. These will serve as vehicles for specific delivery of siRNA to pancreatic beta-cells by targeting recently identified markers on beta-cells (ND-siRNA). In addition, these nanodrugs will function as imaging reporters for in vivo monitoring of delivery by optical and magnetic resonance imaging (MRI). We will first generate luciferase (luc)-conjugated beta-cell-specific moieties that target beta-cells and utilize bioluminescence imaging (BLI) to test their in vivo ability to label beta-cells. Next, we will attach selected targeting moieties to siRNA-containing magnetic nanoparticles and test their ability to deliver siRNA to isolated islets in culture and then in animal models of T1D concurrently with in vivo monitoring of delivery. Genes that are responsible for beta-cell apoptosis and immune recognition will be targeted with siRNA. We expect to observe a decreased T1D incidence in prevention studies and increased number of animals with restored normoglycemia in reversal studies.